Vitamin D and Skin Health

Overview

Sunlight exposure is the primary source of vitamin D for most people. Solar ultraviolet-B radiation (UVB; wavelengths of 290 to 315 nanometers) stimulates the production of vitamin D3 from 7-dehydrocholesterol (7-DHC) in the epidermis of the skin (see Production in Skin) (1). Hence, vitamin D is actually more like a hormone than a vitamin, a substance that is required from the diet. Vitamin D3 enters the circulation and is transported to the liver, where it is hydroxylated to form 25-hydroxyvitamin D3 (calcidiol; the major circulating form of vitamin D). In the kidneys, the 25-hydroxyvitamin D3-1-hydroxylase enzymecatalyzes a second hydroxylation of 25-hydroxyvitamin D, resulting in the formation of 1,25-dihydroxyvitamin D3 (calcitriol, 1α,25-dihydroxyvitamin D]—the most potent form of vitamin D (2). Most of the physiological effects of vitamin D in the body are related to the activity of 1,25-dihydroxyvitamin D3; see the article on Vitamin D. Keratinocytes in the epidermis possess hydroxylase enzymes that locally convert vitamin D to 1,25-dihydroxyvitamin D3(3-5), the form that regulates epidermal proliferation and differentiation (see Metabolism in keratinocytes).

Topical application

Calcitriol (1,25-dihydroxyvitamin D3) has been used topically to treat certain skin conditions, including psoriasis, a skin condition that involves a hyperproliferation of keratinocytes. Several studies found that topical use of calcitriol (3 mcg/g) ointment is safe and may be an effective treatment for plaque-type psoriasis (6-8). The vitamin D analog called calcipotriene or calcipotriol has also been used as a treatment for chronic plaque psoriasis, either alone or in combination with corticosteroids (9, 10).

Production in Skin

Upon exposure to UVB radiation, previtamin D3 is synthesized from 7-DHC in the skin, primarily in keratinocytes of the stratum basale and stratum spinosum layers of the epidermis. Previtamin D3isomerizes to form vitamin D3 (cholecalciferol), which is subsequently transported into the circulation via a binding protein(11). Previtamin D3 can also isomerize to form the photoproducts, tachysterol3 or lumisterol3; the reaction that forms this latter compound is reversible. Both isomers are biologically inactive (i.e., do not enhance intestinal calcium absorption), do not significantly enter the circulation, apparently serve as a mechanism to prevent vitamin D toxicity from prolonged sun exposure, and are probably sloughed off when skin cells are naturally shed (12). Upon exposure to sunlight, vitamin D3 can also be degraded to other photoproducts, including 5,6-trans-vitamin D3, suprasterol I, and suprasterol II (13). Like the active form of vitamin D, some of the mentioned photoproducts may regulate epidermal proliferation and differentiation(14), but elucidation of their biological relevance will require further study.

Numerous variables affect skin synthesis of vitamin D, including latitude, season, time of day, degree of skin pigmentation, age, amount of skin exposed, and sunscreen use. Latitude, season, and time of day create the solar zenith angle, which determines the intensity of sunlight (15). People living in higher latitudes are more at risk for vitamin D deficiency compared to those living in more equatorial latitudes because the sunlight intensity is lower. For those residing in temperate latitudes, time of year influences the ability to generate previtamin D3 in skin. In latitudes around 40 degrees north or 40 degrees south (Boston is 42 degrees north), there is insufficient UVB radiation available for vitamin D synthesis from November to early March. Ten degrees farther north (Edmonton, Canada) or south the “vitamin D winter” extends from October to April (16). Time of day also influences the ability to generate vitamin D in skin, with midday solar radiation being the most intense. Melanin, the dark pigment in skin, competes with 7-DHC for the absorption of UV light and thus acts as a natural sunscreen, reducing the effectiveness of vitamin D production in skin. Therefore, individuals with dark-colored skin require more time (up to ten times as long) to synthesize the same amount of previtamin D3 in skin as those with fair skin (12,17).

According to Dr. Michael Holick, sensible sun exposure, i.e., exposing bare arms and legs to midday sun (between 10 am and 3 pm) for 5-30 minutes twice weekly, may be sufficient to meet vitamin D requirements (18); however, as mentioned above, season, latitude, and skin pigmentation all affect vitamin D synthesis in skin. Other factors influence the ability to produce vitamin D in skin. For example, aging reduces the capacity to synthesize vitamin D in skin since older adults have lower skin concentrations of the vitamin D precursor, 7-DHC, compared to younger individuals (19). Moreover, use of sunscreen effectively blocks UVB absorption and therefore vitamin D synthesis in skin: application of sunscreen with a sun protection factor (SPF) of 8 reduces production of vitamin D in skin by more than 95% (20). Thus, several factors can have a substantial impact on body vitamin D levels through affecting the production of the vitamin in skin.

Biological Activities in Skin

Control of epidermal proliferation and differentiation

The bottom or basal layer of the epidermis, called the stratum basale, consists of a layer of round, undifferentiated keratinocytes that is supported by the underlying dermis. Cells in the stratum basale are constantly proliferating in order to produce new cells that will comprise the upper epidermal layers (23, 24). Once a keratinocyte leaves the stratum basale, it begins the process of differentiation (specialization of cells for specific functions) known as keratinization and also undergoes cornification, a process in which keratinocytes become corneocytes(24; see the article, Micronutrients and Skin Health). Thus, new cells from the stratum basale replace the outer layer of skin cells that is shed over time.

Along with various coregulators, 1,25-dihydroxyvitamin D3 and its receptor, the VDR, regulate the abovementioned processes that replenish skin. In general, vitamin D inhibits the expression of genes responsible for keratinocyte proliferation and induces the expression of genes responsible for keratinocyte differentiation (25). In addition to its steroidhormone actions, vitamin D regulates biochemical steps that result in a cellular influx of calcium, which is important in cell differentiation (26). The processes of epidermal proliferation and differentiation are essential for normal cell growth, wound healing, and maintaining the barrier function of skin. Because uncontrolled proliferation of cells with certain mutations may lead to cancer, vitamin D may protect against certain cancers (see the article on Vitamin D).

Other activities

In skin, the vitamin D receptor (VDR) appears to have other roles that are independent of its association with 1,25-dihydroxyvitamin D3. For instance, the VDR is important in regulating the growth cycle of mature hair follicles (27, 28). Certain mutations in the VDR lead to misregulated gene expression resulting in aberrant hair follicle cycling and alopecia (hair loss) in mice (28, 29) and in humans (30). The VDR also functions as a tumor suppressor in skin (31). The VDR is one of several factors that control these two diverse roles. Moreover, 1,25-dihydroxyvitamin D3 is a potent immune modulator in skin; for general information about vitamin D and immunity, see the article on Nutrition and Immunity.

Functions in Healthy Skin

Photoprotection

Photodamage refers to skin damage induced by ultraviolet (UV) light. Depending on the dose, UV light can lead to DNA damage, inflammatory responses, skin cell apoptosis (programmed cell death), skin aging, and skin cancer. Some studies, mainly in vitro (cell culture) studies (32-35) and mouse studies where 1,25-dihydroxyvitamin D3 was topically applied to skin before or immediately following irradiation (32, 36, 37), have found that vitamin D exhibits photoprotective effects. Documented effects in skin cells include decreased DNA damage, reduced apoptosis, increased cell survival, and decreased erythema. The mechanisms for such effects are not known, but one mouse study found that 1,25-dihydroxyvitamin D3 induced expression of metallothionein (a protein that protects against free radicals and oxidative damage) in the stratum basale (32). It has also been postulated that non-genomic actions of vitamin D contribute to the photoprotection (38); such effects of vitamin D involve cell-signaling cascades that open calcium channels(39).

Wound healing

1,25-dihydroxyvitamin D3 regulates the expression of cathelicidin (LL-37/hCAP18) (40, 41), an antimicrobialprotein that appears to mediate innate immunity in skin by promoting wound healing and tissue repair. One human study found that cathelicidin expression is upregulated during early stages of normal wound healing (42). Other studies have shown that cathelicidin modulates inflammation in skin (43), induces angiogenesis(44), and improves reepithelialization (the process of restoring the epidermal barrier to re-establish a functional barrier that protects underlying cells from environmental exposures) (42). The active form of vitamin D and its analogs have been shown to upregulate cathelicidin expression in cultured keratinocytes (41, 45). However, more research is needed to determine the role of vitamin D in wound healing and epidermal barrier function, and whether oral vitamin D supplementation or topical treatment with vitamin D analogs is helpful in healing surgical wounds.

Conclusion

Sun exposure is the primary source of vitamin D for most people. Upon exposure to ultraviolet-B radiation, previtamin D3 is synthesized in keratinocytes of the epidermis. Previtamin D3 isomerizes to form vitamin D3 (cholecalciferol), which is subsequently transported into the circulation or metabolized by keratinocytes. Keratinocytes can locally convert previtamin D3 to the active form, 1,25-dihydroxyvitamin D3. 1,25-dihydroxyvitamin D3 and its receptor, the VDR, have several biological functions in skin, including regulating the proliferation and differentiation of keratinocytes, hair follicle cycling, and tumor suppression. Some cell culture and rodent studies have shown that 1,25-dihydroxyvitamin D3 exhibits photoprotective effects. Moreover, vitamin D is known to modulate inflammation and may be involved in wound healing. However, more research is needed to understand the exact roles of vitamin D and its receptor in the maintenance of healthy skin.

Authors and Reviewers

Written in November 2011 by: Victoria J. Drake, Ph.D. Linus Pauling Institute Oregon State University

Reviewed in November 2011 by: Daniel D. Bikle, M.D., Ph.D. Professor, Departments of Medicine and Dermatology The University of California, San Francisco

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